Direct Reprogramming of Human Fibroblasts to Hepatocyte-Like Cells by Synthetic Modified mRNAs
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{"title"=>"Direct reprogramming of human fibroblasts to hepatocyte-like cells by synthetic modified mRNAs", "type"=>"journal", "authors"=>[{"first_name"=>"Kamen P.", "last_name"=>"Simeonov", "scopus_author_id"=>"56239303500"}, {"first_name"=>"Hirdesh", "last_name"=>"Uppal", "scopus_author_id"=>"6701861485"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-84903542476", "doi"=>"10.1371/journal.pone.0100134", "sgr"=>"84903542476", "isbn"=>"1932-6203", "pmid"=>"24963715", "issn"=>"19326203", "pui"=>"373419011"}, "id"=>"1310d53a-7d98-3cc1-8069-a9c7025f3705", "abstract"=>"Direct reprogramming by overexpression of defined transcription factors is a promising new method of deriving useful but rare cell types from readily available ones. While the method presents numerous advantages over induced pluripotent stem (iPS) cell approaches, a focus on murine conversions and a reliance on retroviral vectors limit potential human applications. Here we address these concerns by demonstrating direct conversion of human fibroblasts to hepatocyte-like cells via repeated transfection with synthetic modified mRNAs. Hepatic induction was achieved with as little as three transcription factor mRNAs encoding HNF1A plus any two of the factors, FOXA1, FOXA3, or HNF4A in the presence of an optimized hepatic growth medium. We show that the absolute necessity of exogenous HNF1A mRNA delivery is explained both by the factor's inability to be activated by any other factors screened and its simultaneous ability to strongly induce expression of other master hepatic transcription factors. Further analysis of factor interaction showed that a series of robust cross-activations exist between factors that induce a hepatocyte-like state. Transcriptome and small RNA sequencing during conversion toward hepatocyte-like cells revealed global preferential activation of liver genes and miRNAs over those associated with other endodermal tissues, as well as downregulation of fibroblast-associated genes. Induced hepatocyte-like cells also exhibited hepatic morphology and protein expression. Our data provide insight into the process by which direct hepatic reprogramming occurs in human cells. More importantly, by demonstrating that it is possible to achieve direct reprogramming without the use of retroviral gene delivery, our results supply a crucial step toward realizing the potential of direct reprogramming in regenerative medicine.", "link"=>"http://www.mendeley.com/research/direct-reprogramming-human-fibroblasts-hepatocytelike-cells-synthetic-modified-mrnas", "reader_count"=>64, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>3, "Researcher"=>15, "Student > Doctoral Student"=>9, "Student > Ph. D. Student"=>11, "Student > Postgraduate"=>6, "Student > Master"=>4, "Other"=>4, "Student > Bachelor"=>9, "Lecturer"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>3, "Researcher"=>15, "Student > Doctoral Student"=>9, "Student > Ph. D. Student"=>11, "Student > Postgraduate"=>6, "Student > Master"=>4, "Other"=>4, "Student > Bachelor"=>9, "Lecturer"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Engineering"=>4, "Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>12, "Agricultural and Biological Sciences"=>30, "Medicine and Dentistry"=>14, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>4}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>14}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>30}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>12}, "Unspecified"=>{"Unspecified"=>2}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"Netherlands"=>1, "Hong Kong"=>1, "Iran"=>1, "United States"=>2, "Finland"=>1, "Brazil"=>1, "Germany"=>2}, "group_count"=>2}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1564521"], "description"=>"<p>(A) Scheme for producing DNA templates with synthetic UTR and PolyA sequences attached to the ORFs of interest. Primers used in the ORF PCR are gene specific. Primers used in template-tail PCR are independent of the gene and are always the same. Tailed-templates can be generated, purified, and used for overnight <i>in vitro</i> transcription in under two hours of bench time using this method. (B–I) Concentration-dependent translation and proper localization of GFP and nuclear GFP mmRNA at 80 ng, 200 ng, 500 ng, and 1000 ng per well in a 12-well plate. Nuclei are stained blue by Hoechst.</p>", "links"=>[], "tags"=>["Biochemistry", "rna", "RNA transport", "biotechnology", "Bioengineering", "Tissue engineering", "cell biology", "Cellular types", "Animal cells", "stem cells", "Cell potency", "Molecular cell biology", "developmental biology", "Cell differentiation", "Cell fate determination", "genetics", "gene expression", "DNA transcription", "Gastroenterology and hepatology", "Liver diseases", "transfection", "synthetic", "modified"], "article_id"=>1082851, "categories"=>["Biological Sciences"], "users"=>["Kamen P. Simeonov", "Hirdesh Uppal"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0100134.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Production_and_transfection_of_synthetic_modified_mRNAs_/1082851", "title"=>"Production and transfection of synthetic modified mRNAs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-06-25 03:04:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1564522"], "description"=>"<p>(A) Massive induction of hepatic genes, <i>ALB</i> and <i>AFP</i>, within five days of reprogramming (meanSD). Distinct albumin (B), AFP (C), and neutral lipid droplet (D) positive cells also appear within 5 days. Nuclei are stained blue by Hoechst.</p>", "links"=>[], "tags"=>["Biochemistry", "rna", "RNA transport", "biotechnology", "Bioengineering", "Tissue engineering", "cell biology", "Cellular types", "Animal cells", "stem cells", "Cell potency", "Molecular cell biology", "developmental biology", "Cell differentiation", "Cell fate determination", "genetics", "gene expression", "DNA transcription", "Gastroenterology and hepatology", "Liver diseases", "induced", "11tf", "6tf"], "article_id"=>1082852, "categories"=>["Biological Sciences"], "users"=>["Kamen P. Simeonov", "Hirdesh Uppal"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0100134.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Hepatocyte_like_state_induced_by_11TF_and_6TF_within_five_days_/1082852", "title"=>"Hepatocyte-like state induced by 11TF and 6TF within five days.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-06-25 03:04:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1564523"], "description"=>"<p>(A–B) Genes and small RNAs significantly upregulated more than 2-fold over control (red), significantly downregulated more than 2-fold below control (green), and genes without significant changes of 2-fold or more (blue) are plotted logarithmically for 6TF versus vehicle control. Well-known liver and liver-repair associated genes are upregulated (labeled in red), whereas fibroblast associated genes are downregulated (labeled in green). Pluripotency genes and control genes are unchanged (labeled in blue). Well-known hepatic miRNAs, such as miR-122, are upregulated (labeled in red). False discovery rates less than 0.001 for genes and p-values less than 0.05 for small RNAs were deemed significant. (C) Of the top 25 most upregulated genes in reprogrammed cells, twelve (nearly half) are associated with liver or liver-repair (red), four are associated with other endodermal tissues (blue), and four are histones (green). Histone genes were also globally upregulated in reprogrammed cells (D); mean and 75% and 25% quantiles are indicated. The full expression data for all genes (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100134#pone.0100134.s010\" target=\"_blank\">Tables S4</a>, <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100134#pone.0100134.s011\" target=\"_blank\">S5</a>, and <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100134#pone.0100134.s012\" target=\"_blank\">S6</a>) and small RNAs (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100134#pone.0100134.s013\" target=\"_blank\">Tables S7</a>, <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100134#pone.0100134.s014\" target=\"_blank\">S8</a>, and <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100134#pone.0100134.s015\" target=\"_blank\">S9</a>) are provided in the supporting information.</p>", "links"=>[], "tags"=>["Biochemistry", "rna", "RNA transport", "biotechnology", "Bioengineering", "Tissue engineering", "cell biology", "Cellular types", "Animal cells", "stem cells", "Cell potency", "Molecular cell biology", "developmental biology", "Cell differentiation", "Cell fate determination", "genetics", "gene expression", "DNA transcription", "Gastroenterology and hepatology", "Liver diseases", "sequencing", "reprogrammed"], "article_id"=>1082853, "categories"=>["Biological Sciences"], "users"=>["Kamen P. Simeonov", "Hirdesh Uppal"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0100134.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Global_gene_and_small_RNA_sequencing_analysis_of_reprogrammed_cells_/1082853", "title"=>"Global gene and small RNA sequencing analysis of reprogrammed cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-06-25 03:04:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1564524"], "description"=>"<p>Genes annotated as specific to an endodermal tissue, placenta (proxy for cellular immaturity), or soft-tissue (proxy for fibroblasts) were taken from the TiGER database and plotted on a scatterplot (A), with up or down facing triangles indicating significant up or downregulation respectively. As indicated by the lower R<sup>2</sup> value, liver-specific genes were highly dispersed away from control compared to other developmentally related endodermal tissues, such as pancreas. (B) Tissue-specific genes up or downregulated more than 2-fold were displayed as bars. Genes are grouped by tissue and ranked by expression level. Tissues were ordered based on the positive logarithmic area under the curve. The majority of dispersion of liver-specific genes resulted from upregulations. Other endodermal tissues were upregulated and downregulated proportionally. Soft tissue genes were primarily downregulated.</p>", "links"=>[], "tags"=>["Biochemistry", "rna", "RNA transport", "biotechnology", "Bioengineering", "Tissue engineering", "cell biology", "Cellular types", "Animal cells", "stem cells", "Cell potency", "Molecular cell biology", "developmental biology", "Cell differentiation", "Cell fate determination", "genetics", "gene expression", "DNA transcription", "Gastroenterology and hepatology", "Liver diseases", "genes", "dispersion", "upregulation", "endodermal", "tissue-specific"], "article_id"=>1082854, "categories"=>["Biological Sciences"], "users"=>["Kamen P. Simeonov", "Hirdesh Uppal"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0100134.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Liver_specific_genes_show_more_dispersion_and_upregulation_than_other_endodermal_tissue_specific_genes_/1082854", "title"=>"Liver-specific genes show more dispersion and upregulation than other endodermal tissue-specific genes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-06-25 03:04:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1564526"], "description"=>"<p>(A–B) Concurrent staining of reprogrammed samples for AFP and Foxa2 shows that AFP-positive converted cells can exist with or without Foxa2 receipt and expression, indicating that not all six factors of 6TF are necessary for reprogramming. Nuclei are stained blue by Hoechst. (C–E) Consistent loss of <i>AFP</i> induction with removal of <i>HNF1A</i> (blue) from reprogramming cocktails, 6TF, 5TF, and 4TF, with little or no decrease of induction due to removal of other factors. (F–H) Albumin induction measurement shows the same trend as <i>AFP</i> induction. Reprogramming can be achieved with as little as three transcription factors, <i>HNF1A</i> plus two of the following three factors, <i>FOXA1</i>, <i>FOXA3</i>, or <i>HNF4A</i>. Reprogramming could not be achieved at levels resemebling those of 6TF with less than three factors (I–J). Data points shown are meanSD. Stars indicate p-val 0.001. (K) 5TF sample lacking <i>HNF1A</i> clusters with vehicle control separately from 6TF and other 5TF samples and away from hepatocytes based on 33 hepatic genes, supporting the absolute necessity of <i>HNF1A</i>.</p>", "links"=>[], "tags"=>["Biochemistry", "rna", "RNA transport", "biotechnology", "Bioengineering", "Tissue engineering", "cell biology", "Cellular types", "Animal cells", "stem cells", "Cell potency", "Molecular cell biology", "developmental biology", "Cell differentiation", "Cell fate determination", "genetics", "gene expression", "DNA transcription", "Gastroenterology and hepatology", "Liver diseases", "Reprogramming", "interchangeable", "transcription"], "article_id"=>1082856, "categories"=>["Biological Sciences"], "users"=>["Kamen P. Simeonov", "Hirdesh Uppal"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0100134.g005"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_HNF1A_is_necessary_for_reprogramming_and_sufficient_in_combination_with_two_interchangeable_transcription_factors_/1082856", "title"=>"<i>HNF1A</i> is necessary for reprogramming and sufficient in combination with two interchangeable transcription factors.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-06-25 03:04:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1564527"], "description"=>"<p>(A) Cells were reprogrammed with six different combinations of 5TF. The factor missing from each 5TF sample is indicated on the x-axis, and its expression compared to primary hepatocytes is indicated (log2 ratio). The top of each clear bar indicates the level of each factor when delivered to fibroblasts via 6TF; the bottom of each clear bar indicates the endogenous level found in untransfected fibroblasts. Taken together these bars show the compensation each factor receives from the other five factors of 6TF, in relation to hepatocytes, fibroblasts, and 6TF samples. <i>FOXA1</i>, <i>FOXA2</i>, <i>GATA4</i>, and <i>HNF4A</i> were compensated at or above the levels found endogenously in hepatocytes. <i>FOXA3</i> levels were compensated near those of hepatocytes. However, <i>HNF1A</i> received almost no compensation with levels remaining closest to those found in fibroblasts. (B) The first column indicates the effects reprogramming with <i>HNF1A</i> alone exerts on the remaining five factors of 6TF over fibroblast control levels. The remaining columns indicate the effect reprogramming with <i>HNF1A</i> plus one additional factor have on the remaining four factors over the levels found when cells are reprogrammed with <i>HNF1A</i> alone. Upregulations are in red and downregulations in blue. Extensive interactions between the factors are observed. (C) The interactions of the previous matrix are binned into bright red activations (10-fold or more increase in expression), light red prospective activations (2-fold or more increase), and light blue prospective inhibitions (2-fold or more decrease). (D) The interactions defined by the previous binned matrix represented as a diagram between the factors of 6TF during reprogramming. Prospective interactions are dashed.</p>", "links"=>[], "tags"=>["Biochemistry", "rna", "RNA transport", "biotechnology", "Bioengineering", "Tissue engineering", "cell biology", "Cellular types", "Animal cells", "stem cells", "Cell potency", "Molecular cell biology", "developmental biology", "Cell differentiation", "Cell fate determination", "genetics", "gene expression", "DNA transcription", "Gastroenterology and hepatology", "Liver diseases", "transcription"], "article_id"=>1082857, "categories"=>["Biological Sciences"], "users"=>["Kamen P. Simeonov", "Hirdesh Uppal"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0100134.g006"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Robust_compensation_and_interaction_between_the_transcription_factors_of_6TF_/1082857", "title"=>"Robust compensation and interaction between the transcription factors of 6TF.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-06-25 03:04:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1564528"], "description"=>"<p>11TF includes all genes.</p><p>*Included in 6TF.</p><p>Sufficient for hepatic reprogramming when combined with <i>HNF1A</i>.</p><p>Necessary for hepatic reprogramming.</p>", "links"=>[], "tags"=>["Biochemistry", "rna", "RNA transport", "biotechnology", "Bioengineering", "Tissue engineering", "cell biology", "Cellular types", "Animal cells", "stem cells", "Cell potency", "Molecular cell biology", "developmental biology", "Cell differentiation", "Cell fate determination", "genetics", "gene expression", "DNA transcription", "Gastroenterology and hepatology", "Liver diseases", "hepatic"], "article_id"=>1082858, "categories"=>["Biological Sciences"], "users"=>["Kamen P. Simeonov", "Hirdesh Uppal"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0100134.t001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Transcription_factors_used_for_hepatic_reprogramming_/1082858", "title"=>"Transcription factors used for hepatic reprogramming.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-06-25 03:04:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1564529"], "description"=>"<p>R<sup>2</sup> values are calculated based on the log2 of the sequencing expression value for genes and small RNAs. The full expression data for all genes (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100134#pone.0100134.s010\" target=\"_blank\">Tables S4</a>, <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100134#pone.0100134.s011\" target=\"_blank\">S5</a>, and <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100134#pone.0100134.s012\" target=\"_blank\">S6</a>) and small RNAs (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100134#pone.0100134.s013\" target=\"_blank\">Tables S7</a>, <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100134#pone.0100134.s014\" target=\"_blank\">S8</a>, and <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100134#pone.0100134.s015\" target=\"_blank\">S9</a>) are provided in the supporting information.</p>", "links"=>[], "tags"=>["Biochemistry", "rna", "RNA transport", "biotechnology", "Bioengineering", "Tissue engineering", "cell biology", "Cellular types", "Animal cells", "stem cells", "Cell potency", "Molecular cell biology", "developmental biology", "Cell differentiation", "Cell fate determination", "genetics", "gene expression", "DNA transcription", "Gastroenterology and hepatology", "Liver diseases", "genes", "rnas"], "article_id"=>1082859, "categories"=>["Biological Sciences"], "users"=>["Kamen P. Simeonov", "Hirdesh Uppal"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0100134.t002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Global_distribution_of_genes_and_small_RNAs_in_6TF_11TF_and_control_/1082859", "title"=>"Global distribution of genes and small RNAs in 6TF, 11TF, and control.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-06-25 03:04:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1564553", "https://ndownloader.figshare.com/files/1564554", "https://ndownloader.figshare.com/files/1564555", "https://ndownloader.figshare.com/files/1564556", "https://ndownloader.figshare.com/files/1564557", "https://ndownloader.figshare.com/files/1564558", "https://ndownloader.figshare.com/files/1564559", "https://ndownloader.figshare.com/files/1564560", "https://ndownloader.figshare.com/files/1564561", "https://ndownloader.figshare.com/files/1564562", "https://ndownloader.figshare.com/files/1564563", "https://ndownloader.figshare.com/files/1564564", "https://ndownloader.figshare.com/files/1564565", "https://ndownloader.figshare.com/files/1564566", "https://ndownloader.figshare.com/files/1564567"], "description"=>"<div><p>Direct reprogramming by overexpression of defined transcription factors is a promising new method of deriving useful but rare cell types from readily available ones. While the method presents numerous advantages over induced pluripotent stem (iPS) cell approaches, a focus on murine conversions and a reliance on retroviral vectors limit potential human applications. Here we address these concerns by demonstrating direct conversion of human fibroblasts to hepatocyte-like cells via repeated transfection with synthetic modified mRNAs. Hepatic induction was achieved with as little as three transcription factor mRNAs encoding HNF1A plus any two of the factors, FOXA1, FOXA3, or HNF4A in the presence of an optimized hepatic growth medium. We show that the absolute necessity of exogenous <i>HNF1A</i> mRNA delivery is explained both by the factor's inability to be activated by any other factors screened and its simultaneous ability to strongly induce expression of other master hepatic transcription factors. Further analysis of factor interaction showed that a series of robust cross-activations exist between factors that induce a hepatocyte-like state. Transcriptome and small RNA sequencing during conversion toward hepatocyte-like cells revealed global preferential activation of liver genes and miRNAs over those associated with other endodermal tissues, as well as downregulation of fibroblast-associated genes. Induced hepatocyte-like cells also exhibited hepatic morphology and protein expression. Our data provide insight into the process by which direct hepatic reprogramming occurs in human cells. More importantly, by demonstrating that it is possible to achieve direct reprogramming without the use of retroviral gene delivery, our results supply a crucial step toward realizing the potential of direct reprogramming in regenerative medicine.</p></div>", "links"=>[], "tags"=>["Biochemistry", "rna", "RNA transport", "biotechnology", "Bioengineering", "Tissue engineering", "cell biology", "Cellular types", "Animal cells", "stem cells", "Cell potency", "Molecular cell biology", "developmental biology", "Cell differentiation", "Cell fate determination", "genetics", "gene expression", "DNA transcription", "Gastroenterology and hepatology", "Liver diseases", "Reprogramming", "fibroblasts", "hepatocyte-like", "cells", "synthetic", "modified"], "article_id"=>1082875, "categories"=>["Biological Sciences"], "users"=>["Kamen P. Simeonov", "Hirdesh Uppal"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0100134.s001", "https://dx.doi.org/10.1371/journal.pone.0100134.s002", "https://dx.doi.org/10.1371/journal.pone.0100134.s003", "https://dx.doi.org/10.1371/journal.pone.0100134.s004", "https://dx.doi.org/10.1371/journal.pone.0100134.s005", "https://dx.doi.org/10.1371/journal.pone.0100134.s006", "https://dx.doi.org/10.1371/journal.pone.0100134.s007", "https://dx.doi.org/10.1371/journal.pone.0100134.s008", "https://dx.doi.org/10.1371/journal.pone.0100134.s009", "https://dx.doi.org/10.1371/journal.pone.0100134.s010", "https://dx.doi.org/10.1371/journal.pone.0100134.s011", "https://dx.doi.org/10.1371/journal.pone.0100134.s012", "https://dx.doi.org/10.1371/journal.pone.0100134.s013", "https://dx.doi.org/10.1371/journal.pone.0100134.s014", "https://dx.doi.org/10.1371/journal.pone.0100134.s015"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Direct_Reprogramming_of_Human_Fibroblasts_to_Hepatocyte_Like_Cells_by_Synthetic_Modified_mRNAs_/1082875", "title"=>"Direct Reprogramming of Human Fibroblasts to Hepatocyte-Like Cells by Synthetic Modified mRNAs", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-06-25 03:04:19"}

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Relative Metric

{"start_date"=>"2014-01-01T00:00:00Z", "end_date"=>"2014-12-31T00:00:00Z", "subject_areas"=>[{"subject_area"=>"/Biology and life sciences/Anatomy", "average_usage"=>[267]}, {"subject_area"=>"/Biology and life sciences/Genetics", "average_usage"=>[306, 482]}, {"subject_area"=>"/Medicine and health sciences/Anatomy", "average_usage"=>[266]}]}
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